A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by the clustering of depressive episodes during the late menopause transition (the stage of ovarian aging associated with maximal decline of ovarian estradiol secretion) and by estradiol's antidepressant efficacy in perimenopausal depression. Nonetheless, there is no direct evidence that estradiol withdrawal precipitates depressive episodes in those women who develop depression during the perimenopause. In these studies, first we examine the effects of estradiol withdrawal and the recent onset of hypogonadism on mood symptoms in asymptomatic premenopausal women. Second, we investigate what factors influence the development of depression during estradiol withdrawal. We administered a gonadotropin releasing hormone (GnRH) agonist for two to three months to 72 regular cycling, asymptomatic, healthy, premenopausal women. Only four women (approximately 5.6% of the sample) reported clinically significant symptoms of depression and in only one woman were depressive symptoms sustained for two weeks. In contrast to the relative absence of depressive symptoms in these women, we did observe the significant appearance of hot flushes, disturbed sleep, and diminished libido. Consistent with epidemiologic data in perimenopausal women, our findings suggest that neither estradiol withdrawal nor menopausal symptoms are sufficient to induce depressive symptoms in healthy pre-menopausal women. Our study challenges hypotheses suggesting that estrogen withdrawal, hot flushes, or disturbed sleep alone can trigger depression during the perimenopause. The fact that our results stand in marked contrast to numerous case reports of clinically significant depression during GnRH agonist-induced hypogonadism suggests that other factors need to be studied as potential causes for developing depression in the context of estradiol withdrawal and the onset of hypogonadism. Trials that explore the impact of specific risk factors for depression in women receiving GnRH agonists to treat endometriosis or other gynecologic illnesses, moreover, may shed new light on risk factors for depression accompanying ovarian failure and/or hypogonadism. In a second study, we evaluate the effects of the acute withdrawal of estradiol therapy in older postmenopausal women with and those without a past perimenopausal depression. Estradiol withdrawal induces depressive symptoms in women with a past perimenopausal depression, but not in those without such a history. In women with a past depression during the perimenopause, estradiol withdrawal is associated with a significant increase in depressive symptoms compared with those who were maintained on estradiol therapy. Additionally, no significant depressive symptoms emerged in the women lacking a history of depression. This study was recently completed, and our data are consistent with those from epidemiologic studies showing that, for a subgroup of women, the endocrine events of the late menopause transition represent an important trigger for mood destabilization and the onset of depression. Both the markers of this risk and the mechanisms underlying estradiol withdrawal-induced depressive symptoms remain to be identified. The results of the Womens Health Initiative (WHI) have deterred many women from using estrogen therapy, and many women and their physicians are concerned about the long-term risks of estrogen therapy. In a previous study, we demonstrated the antidepressant effects of the short-term administration of estradiol in women with perimenopausal depression. We now are examining the effects on mood and behavior of two compounds that for many women represent alternatives to traditional estrogen therapy. Specifically, selective estrogen receptor modulators (SERMs) and phytoestrogens (plant-derived estrogen-like compounds) have become available and are reported to display both tissue-specific profiles of estrogen agonist and antagonist actions and differential affinities from estradiol for the two forms of estrogen receptor. This study is close to completion, however, preliminary results demonstrate that after eight weeks of either estradiol or raloxifene (but not a plant-based phytoestrogen compound), mood rating scores were significantly decreased compared with baseline scores and significantly lower than scores in women receiving placebo. Thus, we not only have replicated our previous demonstration of the therapeutic efficacy of estradiol in perimenopausal depression, but in addition, we have identified a potential new therapeutic agent (raloxifene) in this condition. Comparable efficacy of raloxifene to that of estradiol would provide an alternative therapeutic option with a more acceptable profile of long-term side effects. As phytoestrogens are already commonly recommended, and widely used for the treatment of mood symptoms, further clarification of their mood effects has significant public health implications. In future studies, we intend to investigate the behavioral relevance of estrogen receptor beta as well as a potential caged form of estradiol with brain-specific estradiol actions in humans. Specifically, we will examine the antidepressant/anxiolytic efficacy of selective estrogen receptor beta agonists (when available for human use) in women with perimenopausal depression. In a separate set of studies in collaboration with Drs. Laurence Nelson and Maya Lodish within NICHHD, we investigate the relationship between ovarian failure and depression in younger women. Karyotypically, normal, 46XX spontaneous (i.e., idiopathic) primary ovarian insufficiency (POI) is a condition in which ovarian failure occurs at an early age. We identified that a lifetime prevalence of depression in adult women with POI is significantly greater than that reported in both the general population, and in gynecologic or general medical outpatient settings. Additionally, first episodes of major depression preceded the date of POI diagnosis in over 70% of women, and, therefore these depressions were not secondary to being diagnosed with POI and its accompanying loss of fertility. Indeed episodes of depression occurred after the onset of menstrual cycle irregularity at a time similar to the onsets of depression in the normally-timed menopause transition. It has been suggested that the accompanying loss of ovarian testosterone production increases the risk for depression in POI (and in perimenopausal depression); however, we have completed a randomized, placebo-controlled, trial of physiologic testosterone replacement in128 women with POI. Results of this trial clearly show the lack of efficacy of testosterone on mood symptoms in POI. We now have initiated a prospective study to evaluate the prevalence of depressive illness in adolescent girls who present with POI. A better understanding of the nature of this association could identify candidate genes and physiological processes that may inform both our understanding of the relationship between depression and POI, as well as the association between depression and the normally-timed menopause transition.